MXPA06012563A - Topical methadone compositions and methods for using the same. - Google Patents

Abstract

Methods and compositions are provided for administering methadone to a subject. Aspects of the invention include employing a topical methadone formulation, e.g., a patch or analogous topical administration formulation. The subject methods and compositions find use in a variety of applications, e.g., in the treatment of a variety of different types of pain.

Description

TOPICAL METHADONE COMPOSITIONS AND METHODS FOR USING THE SAME As a continuation of the U.S.C. 35 § 119 (e), this application claims priority for the filing date of the United States Provisional Patent Application with Series No. 60 / 566,686, filed on April 29, 2004, the description of which is incorporated here as a reference BACKGROUND OF THE INVENTION Pain is a problem that affects a large segment of the population. Pain, such as neuropathic pain and the like, occurs both intermittently and chronically, and may arise in response to a variety of stimulants, including stress, injury, toxins in the environment and the like. Whether chronic or acute, pain can cost a physical, financial and emotional pain, as well as in their families and friends. A variety of therapeutic agents have been developed for use in the treatment of patients suffering from pain, however there is still no safe treatment protocol to effectively treat pain. Some agents, such as aspirin, acetaminophen, vasoconstrictors and NSAIDS, p. Eg, ibuprofen and naprosin, are administered systemically through conventional routes such as oral and intravenous. Despite the widespread use of this form of treatment for a variety of pain, in some cases systemic administration by these conventional routes may not be recommended. For example, oral administration of aspirin may result in upset stomach and discomfort in the patient. In addition, the agent can exert systemic toxicity in the subject, which may outweigh any therapeutic benefit provided by the agent. Finally, not all pain can be effectively managed using conventional agents such as aspirin that are formulated for systemic delivery routes such as oral and intravenous routes of administration. Therefore, interest continues in the identification of topical formulations that are suitable for use in the treatment of pain. Of interest is the administration of formulations that effectively treat pain and provide for the rapid penetration of an effective amount of the active agent through the surface of the skin, for example, to provide rapid pain relief.

References of interest. Patents of interest to the United States include: 6,787,149; 6,720,001; 6,716,449; 6,713,470; 6,638,981; 6,586,478; 6,576,650; 6,562,363; 6,538,008; 6,383,471; 6,143,278; 5,989,585; 5,948,389; 5,935,975; 5,883,115; 5,703,101; 5,589,480; 5,580,876; 5,486,362; 5,260,066 and 4,822,617. Also of interest are: Fullerton et al., Acta. Pharm. Nord. (1991) 3: 181-182; Gagnon et al., Pain Res. Manag. (2003); Ghosh & Bagherian, Pharm. Dev. & Tech. (1996) 285-291; 8 (3): 149-54; Hewitt DJ, Clin J Pain. (2000) 16 (2 Suppl): S73-9; and Morley et al., Palliat. Med. (2003); 17 (7): 576-87.

BRIEF. DESCRIPTION OF THE INVENTION Methods and compositions for administering methadone to a subject are provided. Aspects of the invention include the use of a topical methadone formulation, for example, a patch or an analogous formulation of topical formulation. The methods and compositions of the subject find use in a variety of applications, for example, in the treatment of a variety of different types of pain.

BRIEF DESCRIPTION OF THE DRAWINGS The figures shown here are not necessarily drawn to scale, some components and modalities being exaggerated for clarity. Figures 1A-1C provide the graphical results of several in vivo studies, as reviewed in the Experimental Section below.

DETAILED DESCRIPTION OF THE INVENTION Methods and compositions for administering methadone to a subject are provided. Aspects of the subject's methods include topically applying the methadone formulation that includes an effective amount of methadone, where methadone is the only active agent present in the formulation. The aspects also include contacting a surface of the skin with a thermoplastic elastomeric matrix that includes an effective amount of methadone and maintaining the matrix on the surface of the skin for a sufficient period of time for the methadone to be delivered to the subject. In certain embodiments, the matrix can be a styrene-butadiene-styrene block copolymer matrix or a styrene-isoprene-styrene block copolymer matrix. Topical formulations are also provided which include an effective amount of methadone as the sole active agent and thermoplastic elastomeric matrices including methadone. The methods and compositions of the subject find use in a variety of different applications, for example, the treatment of a variety of different types of pain. Before fully describing the present invention, it should be understood that this invention is not limited to the particular embodiments described, which as such may of course vary. It should also be understood that the terminology used herein is for the purpose of describing only particular embodiments, and is not intended to be limiting, since the competence of the present invention will be limited only by the appended claims. Where a scale of values is provided, it is understood that the invention encompasses each intervening value, up to the tenth of a unit of the lower limit, unless the context clearly indicates otherwise, between the upper and lower limits of the scale and of any other value that is established or that intervenes in that established scale. The upper and lower limits of these minor scales can be independently included in the smaller scales and are also encompassed within the invention, subject to any limit specifically excluded in the established scale. When the established scale includes one or both of the limits, the scales that exclude one or both of those included limits are also included in the invention. The methods described here can be performed in any order of the described events that is logically possible, as well as in the order of events indicated. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, preferred methods and materials are now described.

All publications mentioned herein are incorporated as a reference to explain and describe the methods and / or materials in connection with which the publications are cited. It should be noted that, as used herein and in the appended claims, the singular forms "a" and "the" include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be designed to exclude any optional element. Thus, this statement is intended to serve as a background for the use of exclusive terminology such as "only" "only" and the like, in connection with the description of the claimed elements, or the use of a "negative" limitation. The publications described herein are provided only for description before the filing date of the present application. Nothing in this document should be construed as an admission that the present invention is not entitled to precede those publications by virtue of the foregoing invention. In addition, the publication dates provided may be different from the dates of the current publication, which may require confirmation independently. As briefly described above, the subject invention provides methods and compositions for administering methadone to a subject.

In other descriptive aspects of the invention, the aspects of the methods of the subject are first reviewed in greater detail, followed by a review of other aspects of the invention, for example, pharmaceutical compositions, equipment and systems of the invention, as well as the applications representative in which the methods and compositions find use.

Methods As reviewed above, aspects of the invention provide methods for administering a methadone agent to a subject. As "a methadone agent" is meant methadone (6-dimethylamino-4,4-diphenyl-3-hepatone) and analogs or derivatives thereof. For example, methadone derivatives that are methadone agents include those described in US Patent No. 5,710,256, the disclosure of which is incorporated herein by reference. In certain embodiments, the methadone agent may be normethadone (6-dimethylamino-4,4-d-phenyl-3-hexanone), or a methadone intermediate such as 4-cyano-2-dimethylamino-4,4- diphenylbutane, where it should be understood that all are contemplated by the subject of the invention and are included as a reference to methadone unless otherwise indicated. By "administering" is meant to deliver an amount of methadone to a subject, wherein embodiments of the invention include systematically administering an amount of methadone to a subject. By administering systematically, it is understood that the agent is not acting only locally where the patch is administered, for example, in the tissues underlying the skin region below the patch, but that the active medication (methadone) is delivered in a way that reaches many disparate parts of the subject through circulation. Generally, the "subjects" of the invention are "mammals," a term used to broadly describe organisms that are within the mammalian class. Of interest is the treatment of primates with the methods of the subject (for example, humans, chimpanzees and monkeys), where the methods of the subject are particularly suitable for use in the treatment of humans suffering from neuropathic pain, nociceptive pain, pain inflammatory, acute pain, chronic pain, pain from cancer, and other types of pain, as described above. A feature of the embodiments of the invention is that the agent is administered systemically to the subject in a manner that provides a therapeutic level of the agent in the subject's blood for a long period of time. Although the "therapeutic level" that is achieved in a given modality can vary, in certain representative modalities the therapeutic level of analgesia of the agent that is achieved through the practice and the methods of the subject is of a blood level of the agent that is on the scale of from about 50 ng / ml to about 500 ng / ml. The therapeutic level for analgesia that is achieved following a given administration can last for an extended period of time; for example, from about 4 hours to about 24 hours. In certain embodiments, administration according to the methods of the subject results in a blood level profile of the agent characterized by at least a first phase characterized by an initial increase in blood level through an initial period of time. on the scale from 0.1 to about 10 hours, such as from about 0.25 to about 8 hours, followed by a second phase characterized by a gradual decrease in the period over an extended period of time, for example, on the scale from about 2 hours to about 24 hours or more, where the second phase is longer than the first phase by at least about 2 bends, such as by at least about 5 bends or even of 10 folds or more. A feature of the embodiments of the invention is that the agent is administered as described above using a topical formulation. As reviewed in more detail below, embodiments of the invention provide the above administration characteristics from a topical formulation having a dose or amount of a methadone agent that is in the ratio of from about 0.10% to about of 30.0% (w / w) of the methadone agent, for example, from about 0.5% to about 15.0% (w / w), for example, from about 1.0% to about 5.0% (w / w) . In the broadest sense, any suitable topical methadone formulation that provides the required penetration of the methadone in the formulation through the surface of the skin into the subject's target area can be employed. The topical formulation can be a gel, lotion, aerosol, ointment, cream, patch, tape, plaster and the like. In certain embodiments, methadone is present in a matrix, where the matrices of interest include, but are not limited to, macromolecular matrices such as thermoplastic elastomeric matrices, for example, styrene-butadiene-styrene block copolymer matrices, matrices of styrene-isoprene-styrene block copolymer, and the like. In certain embodiments, topical methadone formulations are those in which the only active agent is an active methadone agent. As such, these embodiments are characterized in that no other active agent is present in the topical formulations. The topical methadone formulations employed in the subject methods are formulations that include an effective amount of a methadone agent, where, in many embodiments, the agent is the only active agent in the topical formulation. Accordingly, as used herein, a "topical methadone formulation" and the like terms are understood as a formulation that includes a methadone agent and that is capable of administering the methadone agent to a subject through the surface of the body part of the subject. Although the amount of active agent n the subject formulations may vary, in many embodiments the amount of methadone agent present in the topical formulations is an amount that is effective to treat a subject against pain, including an effective amount to reduce the less the frequency and / or the intensity of the pain, that is, is present in the formulations in at least an amount that reduces the pain. In certain embodiments, methadone may be present in a preventive amount of pain such that the magnitude or intensity of the pain is not only reduced, but the pain is completely eliminated, at least for a period of time, through the amount of active agent present in the formulation. In certain embodiments, the amount of methadone present may be sufficient to act only locally, to act only systemically, or it may be in an amount that is sufficient to act both locally and systemically to treat the pain. As reviewed above, in many modalities the administration is systemic. In this way, the methadone may be in an amount sufficient to act as a μ-opioid agonist and / or as an antagonist of the N-methyl-D-asparatate receptor ("NMDA"), locally, systemically, or both locally and systemically. The modalities may include from about 0.10% to about 0.0% (w / w) of the methadone agent, for example, from about 0.5% to about 15.0% (w / w), for example, from about 1.0. % up to about 5.0% (weight / weight). As mentioned above, topical methadone formulations can be in any suitable form that allows the methadone agent to be effectively delivered topically. "Topical" or "topical administration" and analogous terms are used here in their conventional meaning, to refer to direct contact with the surface of the body, such as skin, eyes, mucosa and lips, which may be in or on any part of the body including, but not limited to, the epidermis, any other epidermis or any other body tissue. Topical administration or application means direct contact of the methadone formulation with the tissue, such as the skin or membrane, such as the cornea, or the oral, vaginal or buccal mucosa. Topical administration also includes application to hardened tissue such as teeth and skin appendages such as nails and hair. In many embodiments, topical formulations are those formulated to be applied to an intact, keratinized skin surface of a subject. The methadone agent can be formulated into topical preparations in the solid, semisolid, liquid or gaseous forms, such as, but not limited to, gels, lotions, emulsions, creams, pastes, jellies, paints, powders, plasters, ointments, sprays such as aerosols, or it can have the shape of a "finite" carrier, that is, a non-spreading substance that retains its shape, such as a patch, a bioadhesive, clothes and bandages, for example, present on a surface in a support. Topical formulations of the subject can be aqueous or non-aqueous and can be formulated as a solution, an emulsion or a suspension. Topical formulations may include one or more of a penetrating agent, a thickener, a diluent, an emulsifier, a dispersing aid, or a binder. For example, a topical methadone formulation can be formulated with, or for use with, a penetration enhancer. Penetration enhancers, which include chemical penetration enhancers and physical penetration enhancers, facilitate delivery of the compound through the skin and can also be referred to interchangeably as "permeation enhancers". Physical enhancers of penetration include, for example, electrophoretic techniques such as iontophoresis, use of ultrasound (or "phonophoresis") and the like. Chemical penetration enhancers are agents that are administered either before, or following immediately upon administration of the active agent, which increase the permeability of the skin, particularly the stratum corneum, to provide improved penetration of the active agent through of the skin. Compounds that can be used to improve skin permeability include, but are not limited to, dimethylsulfoxide sulfoxides (DMSO) and decimethylsulfoxide (C-io MSO); ethers, such as diethylene glycol monoethyl ether, dekaxyethylene oleyl ether, and diethylene glycol monomethyl ether; surface agents such as sodium laurate, lauryl sodium sulfate, cetyltrimethylammonium bromide, benzalkonium chloride, Poloxamer (231, 182, 184). Tween (20, 40, 60, 80) and lecithin; 1-substituted azacycloheptan-2-ones, particularly 1-n-dodecylcyclazacycloheptan-2-one; alcohols, such as ethanol, propanol, octanol, benzyl alcohol, and the like; petrolatums, such as petroleum jelly (petrolatum), mineral oil (liquid petrolatum), and the like; fatty acids such as C8-C-? 2 and other fatty acids (for example, isostearic acid, octanoic acid, oleic acid, lauric acid, valeric acid); C8-C22 fatty alcohols (for example, oleyl alcohol, lauryl alcohol); lower alkyl esters of C 1 -C 22 fatty acids and other fatty acids (for example, ethyl oleate, isopropyl myristate, butyl stearate, methyl laurate, isopropyl myristate, isopropyl palmitate, methylpropionate, ethyl oleate); monoglycerides of C8-C22 fatty acids (eg, glyceryl monolaurate); polyethylene ether glycol of tetrahydrofurfuryl alcohol; 2- (2-ethoxyethoxy) ethanol; monomethyl glycol ether; alkylaryl ethers of polyethylene oxide; polyethylene oxide monomethyl ethers; polyethylene oxide dimethyl ethers; lower alkyl esters of C6-C8 diacids (eg, diisopropyl adipate); ethyl acetate; acetoacetic ester; polyols and esters thereof such as propylene glycol, ethylene glycol, glycerol, butanediol, polyethylene glycol, and polyethylene glycol monolaurate; amides and other nitrogen compounds such as urea, dimethylacetamide (DMA), dimethylformamide (DMF), 2-pyrrolidone, N-alkylpyrrolidone, for example, 1-methyl-2-pyrrolidone; ethanol amine, diethanol amine and triethanolamine; terpenes; alkanones, and organic acids, particularly salicylic acid and salicylates, citric acid and succinic acid. Other chemical and physical enhancers of penetration are described, for example, in Transdermal Delivery of Drugs, A. F. Kydonieus (ED) 1987 CRL Press; Percutaneous Penetration Enhancers, eds. Smit et al. (CRC Press, 1995); Lenneruas et al., J Pharm Pharmacol 2002; 54 (4): 499-508; Karande et al., Pharm Res 2002; 19 (5): 655-60; Vaddi et al., J Pharm Sci 2002 July; 91 (7): 1639-51; Ventura et al., J Drug Target 2001; 9 (5): 379-93; Shokri et al., Int J Pharm 2001; 228 (1-2): 99-107; Suzuki et al., Biol Pharm Bull 2001; 24 (6): 698-700; Alberti et al., J Control Reléase 2001; 71 (3): 319-27; Goldstein et al., Urology 2001; 57 (2): 301-5; Kiijavainen et al., Eur J Pharm Sci 2000; 10 (2): 97-102; and Tenjarla et al., Int J Pharm 1999; 192 (2): 147-58.

When a chemical penetration enhancer is employed, the penetration enhancer is selected for methadone compatibility, and is present in an amount sufficient to facilitate delivery of the methadone c through the skin of a subject. Topical application of the methadone formulations of the subject can be carried out through a variety of methods, including, but not limited to, rubbing, sprinkling, or the like, of a formulation of the invention on an intact skin area, positioning a matrix (such as a macromolecular matrix, for example a thermoplastic elastomer matrix, and the like) that includes an amount of methadone over an area of intact skin, and the like. Methadone formulations suitable for transdermal administration may also be delivered by iontophoresis or the like. As mentioned above, the modalities include topical methadone formulations, formulated as applicator sticks, solutions, suspensions, emulsions, gels, lotions, creams, ointments, pastes, jellies, paints, powders, sprays such as aerosols, emulsions, plasters, etc. . In certain embodiments, the methadone formulations may be in the form of an adhesive base such as a pressure-sensitive adhesive base, for example, a thermoplastic elastomeric matrix and the like, for example, as a discrete patch, bioadhesive or film or plaster or similar, adapted to remain in intimate contact with a surface of a part of the body such as the epidermis of a subject for a period of time. For example, such matrices may include a base or matrix component, for example, the macromolecular matrix such as a thermoplastic elastomer component, where an effective amount of methadone is retained. The base or layer of the matrix can be operatively associated with a support or backing. Modalities include macromolecular matrices that include an effective amount of methadone. The macromolecular substance that can be used according to the subject of the invention can be a natural macromolecular substance or a synthetic macromolecular substance. It can be adhesive or non-adhesive, for example, it can be inherently adhesive or inherently non-adhesive. If a non-adhesive substance is used, an adhesive component can be added to impart adhesive properties to achieve an adequate level of adhesiveness. Examples of macromolecular substances that may be employed in the subject of the invention include, but are not limited to, natural rubber, polyisoprene, polybutadiene, styrene-isoprene-styrene block copolymers ("SIS"), styrene-block copolymers. butadiene-styrene ("SBS"), polyacrylic esters, polymethacrylic esters, methacrylic ester copolymers of acrylic ester, copolymers of acrylic vinyl ester acrylic acid copolymers, petroleum resins, and the like. These macromolecular substances can be used alone or in combination of two or more, where in many embodiments two or more macromolecular substances can be used as a matrix. The matrices are typically easily released from the skin without appreciable pain or irritation. Although the embodiments of the methadone-containing matrix compositions of the subject are inherently adhesive to a surface of the skin, they are advantageously cohesive enough to be easily removed from the surface of the skin. In many embodiments, a thermoplastic elastomer is a main component of a matrix. The thermoplastic elastomer is generally a block copolymer which can be represented by the following general formula: ABA or (AB-) nx where "A" is substantially a polymer block of aromatic compound substituted with monovinyl, "B" is a block of substantially conjugated diolefin polymer, "n" is an integer from about 3 to about 7, and "X" indicates a residue derived from a polyfunctional compound with which chains (AB) of polymer 3-7 are combined (n ). The block copolymer of the formula can represent a TR block copolymer, a radial block copolymer TR or a mixture thereof in certain embodiments. The aromatic compounds above, substituted with monovinyl include, but are not limited to, styrene, o- or p-vinyltoluene, methylstyrene and ethylstyrene. Conjugated diolefins include, but are not limited to, 1-3-butadiene, 1,3-pentadiene and isoprene. A combination of styrene with 1,3-butadiene, and a combination of styrene with isoprene, are combinations that can be employed. The embodiments include matrices of block A which may be a styrene polymer, and block B which is a polymer of isoprene or butadiene. The terminal block A in the above block copolymer can be contained therein in an amount in the ratio of from about 10% to about 80% by weight of the block copolymer, for example, from about 14% to about 22% Other optional components of a matrix (or other topical methadone formulations) can include, but are not limited to, solvents, resins, waxes, for example liquid paraffin and the like, antioxidants, for example dibutylhydroxytoluene and the like, etc., as well as other optional components described here. For example, exemplary solvents that may be employed include, but are not limited to, mineral oil, N-methyl-2-pyrrolidone, diisopropyl adipate, DEET, PEG, Di (propylene glycol), dehydrated alcohol, water, and the like . In certain embodiments, the formulations include DEET, where the DEET is present in an amount in the ratio of from about 1 to about 30%, including from about 5 to about 25%, including from about 5 to about 20%, such as from about 7.5 to about 15%, for example, 10%. Exemplary resins that can be employed include, but are not limited to, saturated hydrocarbon-based alicyclic resin, hydroxyl-terminated polybutadiene, and the like.

In certain embodiments, a topical methadone formulation that is used in the subject matter of the invention can be prepared from water-insoluble components, or salts thereof, such as aqueous base emulsions. In those embodiments, the formulations may contain a sufficient amount of pharmaceutically acceptable emulsifying agent to emulsify the component (s). Useful emulsifying agents include, but are not limited to, phosphatidyl hills, lecithin, and the like. Other additives, such as pH adjusting additives, can also be included in methadone formulations. For example, pH adjusting agents include, but are not limited to, acids, such as hydrochloric acid, bases or regulators, such as sodium lactate, sodium acetate, sodium phosphate, sodium citrate, sodium borate, or sodium gluconate. In addition, microbial preservatives can be used. Microbial preservatives that may be employed include, but are not limited to, methylparaben, propylparaben and benzyl alcohol. In certain embodiments, a given matrix may be present on a backup or support layer. The support is generally made of a flexible material that is capable of adjusting with the movement of the human body and includes, for example, various non-woven fabrics, woven fabrics, spándex, flannel, or a laminate of these materials with polyethylene film, film of polyethylene glycol terephthalate, polyvinyl chloride film, ethylene-vinyl acetate copolymer film, polyurethane film, and the like. By "flexible" it is meant that the support can be curved or bent substantially without breaking, tearing, derailing, etc. The support can be porous or non-porous, but is typically non-porous. In certain embodiments, the backing layer is substantially impermeable to the composition of the matrix, methadone and fluids, for example, any fluid exuded from the application site. This impermeability of the backing increases the effectiveness and efficiency of the composition of the matrix containing methadone. For example, the substantial impermeability to methadone serves to improve or increase the penetration of methadone into the skin. The length and width dimensions of the support are typically substantially commensurate, including commensurate with accuracy, with the length and width dimensions of the matrix composition containing the methadone with which it is associated. The support layer may have a thickness in the range from about 10 μm to about 1000 μm, but may be less than 10 μm and / or greater than 1000 μm in certain embodiments. In addition to the methadone-containing matrix composition and the support layer (if present), a release film may be positioned on the surface of the methadone-containing matrix composition opposite the backing provided to protect the environment from the environment. matrix composition containing methadone. The release film can be any convenient material, where representative release films include polyesters, such as PET or PP, and the like. A transdermal drug delivery system with matrix / backing layer containing methadone, can be manufactured using any convenient protocol. A convenient protocol for the manufacture of the transdermal drug delivery system with matrix / backing layer containing methadone includes preparing a paste-like mixture through the uniform mixing of the aforementioned ingredients, and then covering the paste on a support , followed by cutting the resulting product to the specified size to obtain the transdermal delivery system of the drug with matrix / backing layer containing the desired methadone. The amount of matrix layer containing methadone present in a backing layer may vary, so that in certain embodiments the amount may be in the ratio of from about 500 grams / meter2 to about 10., 000 grams / meter2. The shape of the drug transdermal delivery system with matrix / backing layer containing methadone may vary, where representative forms include, but are not limited to, square, rectangular, oval, circular, triangular, etc. The size of a transdermal delivery system of the drug with backbone layer containing methadone can also vary, where in many embodiments the size can range from about 1 to about 1000 cm2 or more, for example, in certain embodiments are on the scale of from about 10 to about 300 cm2, for example, from about 20 to about 200 cm2, for example, from about 130 cm2 to about 150 cm2. In certain embodiments, the area of the surface is sufficient to cover a complete part of a subject. Accordingly, the surface area can be in the range of from about 1000 cm2 to about 5000 cm2 or more, where in certain embodiments the dimensions of a transdermal drug delivery system with matrix / backup layer that Methadone content of the subject can be about 1 m by about 1 m. For a more detailed description of the manufacturing protocol, see for example US Patent No. 5,827,529, the disclosure of which is incorporated herein by reference. An exemplary method for manufacturing a transdermal drug delivery system with matrix / backing layer containing methadone includes incorporating the methadone into a macromolecular matrix such as a SIS block copolymer matrix or the like, and spreading the resulting preparation over the surface of a backup layer to provide a matrix layer containing methadone on the backup layer. A delineator or releasable cover can be applied to the matrix containing methadone present on the backing layer. The resulting transdermal system can be cut to smaller sizes and / or in various forms, if desired. For example, a mixture containing one or a combination of thermoplastic elastomers and one or more other components such as those described herein, can be heated to soften or melt the mixture. Then the resulting mixture can be cooled and an appropriate amount of methadone can be added to the mixture and mixed for a period of time to disperse the methadone through the mixture. The methadone-containing matrix thus obtained can then be extended or covered on a support with the use of a medical roller, a reverse roller applicator, a slot die applicator, a knife applicator, and the like, it should be noted that the protocols above manufacturing are only representative. Any suitable protocol that is capable of producing a transdermal delivery system of the drug with matrix backing layer containing methadone of the subject matter of the invention, can be employed. Regardless of the form of the methadone topical formulation, when practicing the methods of the subject, a topical methadone formulation of the subject is applied to the surface of a subject's body, eg, a surface of the subject's skin, in a manner sufficient to provide penetration of an effective amount of methadone through the skin. The topical formulation of methadone can be applied directly to the source of the pain or directly to the surface of the skin associated with the pain, or it can not be applied directly to the source of the pain. In modalities in which a transdermal drug delivery system with matrix / backup layer containing methadone is employed, the system is first removed from any packaging that may be present, and then the protective layer, if present, is removed. thus exposing the matrix containing methadone. The transdermal drug delivery system with matrix / backing layer containing methadone is then positioned on a surface of the body such as a surface of the skin of a subject. As mentioned above, in certain embodiments the delivery systems of the methadone-containing matrix are self-adhesive, for example, inherently adhesive, and can therefore be fixed in a position, for example, removably attached to the surface of the skin, without use of additional adhesives or other methods to keep the methadone-containing matrix in place over the formulation. As mentioned above, in certain embodiments the topical formulation may be in the form of a cream or the like, and thus dispensed from the dispensing package in which it is provided and spread on a surface of the body such as a surface of the skin and then optionally occluded with a matrix (which may or may not be present in a support) that does not include methadone in the matrix, such as a macromolecular matrix as described above that lacks any methadone (eg, a "blank matrix"). That is, in certain embodiments, a matrix layer that includes or does not include methadone can be positioned on a surface of the skin that has a methadone formulation applied topically immediately applied thereto. A topical methadone formulation of the subject matter of the invention can be employed to act locally (peripherally), systemically, or locally and systemically, which is determined at least in part by the methadone formulation used in particular and the like. Accordingly, in certain embodiments the methods of the subject include I applying topically an effective amount of methadone to a surface of the skin directly on the source of the pain, to treat a subject for pain acting only locally as a local agonist of the pain. mu-opioid and a local NMDA receptor antagonist. In certain embodiments, methods of the subject include topically applying an effective amount of methadone to a surface of the skin, but not directly over the source of the pain, to treat the subject for pain acting only systemically (such as to result in a low systemic activity) as a systemic agonist of the mu-opioid and a systemic antagonist of the NMDA receptor. In other certain embodiments, methods of the subject include topically applying an effective amount of a methadone agent to a surface of the skin directly on the source of the pain, to treat a subject for pain acting locally as a local agonist of the pain. -opioid, locally as an NMDA receptor antagonist, systemically as a mu-opioid agonist and systemically as an NMDA receptor antagonist. The topical methadone formulation can also be applied to any convenient topical site. Topical sites of interest include, but are not limited to: arms, legs, joints, face, neck, torso, etc. The topical formulation can be applied to one or more different regions, depending on the origin of the pain. The amount of surface area on which a methadone formulation is applied may vary depending on the particular condition of the pain being treated, the site of application, etc. The surface area that is covered by the topical formulation should be sufficient to provide effective and efficient administration of a desired amount of methadone and in any of the modalities can be on the scale of from about 1 to about 100 cm2 or more , for example, in certain embodiments it ranges from about 10 to about 300 cm2, for example, from about 20 to about 200 cm2, for example, from about 130 cm2 to about 150 cm2. In certain modalities, the area of the surface is sufficient to cover the entire part of a subject. Accordingly, the surface area can be in the range of from about 1000 cm2 to about 5000 cm2 or more, where in certain embodiments the surface on which the topical formulation is applied can be about 1 m for about 1 m. By practicing the methods of the subject, a topical formulation can be applied only once or a plurality of times over a period of time, where the dosing schedule can be daily, weekly, biweekly, monthly, etc. For example, certain topical formulations may be applied two or more times a day, two or more times per week, etc. The amount of methadone agent that is applied is sufficient to provide the desired reduction in at least one aspect of pain, for example frequency and / or intensity of pain. The exact amount of topical methadone applied can be determined empirically, for solutions, dispersions, gels, lotions, creams and the like, the methadone formulation will be spread over the region and on top of it a cover will be optionally applied, as mentioned above . For methadone formulations in the form of a transdermal system that includes a matrix such as a SIS block copolymer matrix and / or SBS present in a support, a system of appropriate size will be placed on the region comprising the application site such as a skin site. The formulation is held in place for a sufficient period of time for the desired improvement in symptoms to occur, for example, pain reduction. The particular period of time during which the formulation is maintained at the site of application depends on a variety of factors such as, but not limited to, the nature of the pain, the subject, for example the sensitivity of the subject to methadone, etc. ., but generally the formulation is held in place for at least about 30 min., for example, at least about 1 hr, eg, at least about 4 hr, where the formulation can be held in place during as much as about 8 hr to about 12 hr or more, and in certain modalities the time period can last from about a few hours to about a few days or more, for example, about one or more days, for example, about a week or more. These periods of time may represent periods of total treatment time; that is, the total amount of time that an area of the skin is treated according to the methods of the subject, or it may be a period of time of a first treatment and / or of any successive treatments to a particular site of application, of So that the successive treatments according to the methods of the subject can be carried out immediately after a first treatment in a particular place of application, for example, immediately after or after having passed a period of time. Successive treatments may include the application of an effective amount of the same topical methadone formulation used in a previous application, an effective amount of a methadone dosage different from that used in the previous application, an effective amount of the same methadone formulation present in a different form of topical formulation (eg, a cream instead of a transdermal matrix system), etc. Accordingly, in certain embodiments immediately or after a sufficient period of time has elapsed, the methods of the subject may be repeated one or more times so that a topical methadone formulation (which may be a methadone formulation) may be applied to an application site. the same methadone formulation or a different one from the one previously used). For example, when transdermal drug delivery systems are used with matrix / backup layer containing methadone, the amount of time in which a transdermal drug delivery system with matrix / backup layer containing methadone can be replaced with another, for example, over the course of a day, can be from about 1 time to about 2 times, and in certain modalities a transdermal delivery system of the drug with matrix / backup layer containing methadone can be replaced more twice in a day. For example, in certain modalities a system can be changed about once every 24 hours, approximately. In certain modalities, a system can be used only during work hours and is removed to sleep. The modalities include the gradual decrease over time of the strength of the methadone employed, by applying decreased amounts of methadone to the subject. For example, using a system of a first methadone dosage amount over a period of time (or a plurality of such systems), for example, every day for about 1 to about 4 months, and then a second system, or a system of lower methadone strength (or a plurality of such systems), which may be followed by a third system or a system of lower methadone strength (or a plurality of such systems), etc., where the effective amount of methadone that is delivered to a subject is gradually decreased over time using methadone formulations with varying amounts of methadone. In embodiments in which a transdermal drug delivery system with matrix / backup layer containing methadone is used, the drug transdermal delivery system with matrix / backup layer containing methadone is removed from the application site once a sufficient amount of time has elapsed (and replaced with another or other methadone formulations, if desired). The nature of the drug transdermal delivery system with matrix / backing layer containing methadone allows it to be easily and non-traumatically removed from the application site, simply by detaching the transdermal delivery system of the drug with matrix / backing layer containing methadone of the site. When removed, the transdermal delivery system of the matrix drug / backing layer containing methadone is removed intact, ie the transdermal drug delivery system with matrix / backing layer containing methadone leaves no residues at the site. A characteristic of the methods of the subject is that, upon application of the methadone topical composition, the methadone agent present there penetrates the surface of the body such as the surface of the skin to achieve the desired result, for example, treating the subject for pain. The embodiments of the subject of the invention include one or more additional steps, for example, diagnosing the subject as a subject in need of administration of a methadone agent. In certain embodiments, the topical formulation that is employed is one that has been stored for an extended period of time, for example, at least about 1 month or more, at least about 2 months or more, at least about 3 months or more, at least about 4 months or more, at least about 5 months or more, at least about 6 months or more, at least about 9 months or more, at least about 12 months or more, at least about 24 months or more, etc., under standard storage conditions, for example, as reported in the Experimental Section below, or conditions that are considered in the art to be analogous to them. For representative conditions, see also the Experimental Section, below (for example, at a temperature of about 25 ° C +/- 2 ° C). A given formulation is considered stably stored if the amount of active agent after the storage time period is at least about 85%, such as at least about 90%, including at least about 95%, for example, as determined using the HPLC protocol described in the Experimental Section below.

Utility Applications of subject methods include topically administering an effective amount, ie, a therapeutically effective amount, of a methadone to a subject. By "effective amount" and analogous terms is meant a dosage sufficient to achieve the desired result, for example, treating the subject for pain for a period of time. The effective amount will vary with the age and physical condition of the subject, the type and severity of the pain being treated, the duration of the treatment, the nature of any concurrent treatment, the form of the methadone formulation, the pharmaceutically acceptable carrier. which is used, if used, and analogous factors within the knowledge and experience of those skilled in the art. The dosages can be determined in accordance with routine pharmacological procedures known to those skilled in the art. The frequency of administration of topical methadone formulations of the subject may take from about 1 time a day to multiple times a day, for example, about 2 times or more per day or as necessary to treat or prevent , controlling or otherwise managing pain, for example, at least reducing the frequency and / or intensity of pain over a period of time. The duration of the therapy depends on the type of pain treated, etc., and can be from as little as about 24 hours (or less in some modalities) to as much as the subject's life. The above-described invention finds use in a variety of different applications, including, but not limited to: treatment of a variety of different conditions, eg, drug addiction, pain, etc., where the methods of the subject are employed in many representative modalities to treat a subject suffering from pain. The methods of the subject can be used to treat a variety of different types of pain including, but not limited to, neuropathic pain, nociceptive pain, inflammatory pain, acute pain, chronic pain, pain from cancer, and other types of pain. The methods of the subject can also be used as a safe and effective treatment for narcotic withdrawal and dependence, for example, to treat a subject for opioid addiction such as heroin addiction and the like. A variety of subjects are treatable with the methods of the subject.

Generally those subjects are "mammals," a term that is used widely to describe organisms that are within the mammalia class. Of interest is the treatment of primates with the methods of the subject (for example, humans, chimpanzees and monkeys), where the methods of the subject are particularly suitable for use in the treatment of humans suffering from neuropathic pain, nociceptive pain, inflammatory pain , acute pain, chronic pain, pain from cancer, and other types of pain, as described above.

As mentioned above, the subject of the invention finds use in the treatment of pain. By "treatment" and analogous terms is meant at least one improvement of pain over a period of time, wherein improvement is used in a broad sense to refer to at least a reduction in the magnitude or intensity and / or frequency of pain as it is evaluated according to the pain assessment tool commonly known as the Pain Relief Record protocol (where 0 is the worst pain, 1 is unchanged, 2 is slight improvement, 3 is moderate improvement, 4 is much improvement, 5 is complete relief). In many embodiments, the magnitude of the reduction in pain intensity may be at least about 10% (light relief), eg, at least about 25% (light-moderate relief), for example, from less about 50% (moderate relief), where the magnitude of the reduction can be as much as 75%, close to 80%, close to 95% or greater (much relief), including a complete cessation of pain (total relief) . The period of time may vary, where in certain modalities the time period can be from about 1 hour to about 24 hours or more, for example, a period of time can be about 3 hours, for example, at least about 6 hours in certain modalities, for example, of at least about 12 hours or greater, for example, of about 16 hours, of about 24 hours, or more. As used herein, the treatment also includes situations in which pain is completely inhibited, for example, preventing it from occurring, or stopping, for example, ending, so that the subject no longer has the pathological condition, less during a period of time. As such, the application and maintenance of the topical methadone formulation, as described above, results in at least an improvement or reduction in the magnitude and / or frequency of pain, including a complete cessation or removal of pain during a period of time, for example, for about 1 hour or more, for example, a period of time which may be about 3 hours, for example, of at least about 6 hours in certain modalities, for example, from less about 12 hours or more, for example, about 16 hours, about 24 hours, or more. In many modalities, the intensity of the associated pain is at least reduced, whereas in certain modalities the pain can be completely eliminated or inhibited, for example, it is prevented from occurring, or stopped, for example, it is terminated, so that the subject no longer suffers from pain, at least for a period of time that can be about 3 hours, for example, at least about 6 hours in certain modalities, for example, of at least about 12 hours or more, for example, about 16 hours, about 24 hours, or more.

Topical Methadone Formulations Topical methadone formulations are also provided which include an effective amount of a methadone active agent, as described above, where topical methadone formulations are present in a configuration that is designed for use in the treatment of pain. according to the methods of the subject. For example, topical methadone formulations can take the form of a gel, lotion, spray, paint, ointment, cream, patch, tape, poultice and the like, as described above. In certain embodiments, the methadone formulations are present as a macromolecular matrix, where the matrices of interest include, but are not limited to, thermoplastic elastomer matrices such as styrene-butadiene-styrene block copolymer matrices, copolymer matrices of styrene-isoprene-styrene block and the like, which may be present on a backing layer. In certain embodiments, methadone is the only active agent present in the topical preparation and in other embodiments more than one active agent (methadone and one or more other active agents) may be present. The embodiments include transdermal drug delivery systems with matrix / backing layer containing methadone and analogous structures which are specifically shaped with respect to the meta epidermal location of their intended application, eg, to cover the required surface area. of the target location as described above, for example, as a rectangular, square, round, oval or other form configured to cover a target application site of the surface of the skin in a manner described above. The amount of active methadone present in the formulation may vary depending on the nature of the formulation, but in many embodiments it may be in the ratio of from about 0.1% to about 30.0% (w / w), for example, from near from 0.5% to about 15.0% (w / w), for example from about 1.0% to about 5.0% w / w.

Teams are also provided to practice the methods of the subject. The equipment of the subject can vary much with respect to the components that include. The subject team includes at least one topical methadone formulation to be used in practicing the subject's methods. The topical methadone formulation can be in any suitable form, for example, a gel, lotion, spray, ointment, cream, patch, paint, tape, poultice and the like, as described above. In certain embodiments, a kit can include methadone formulations in the form of a macromolecular matrix, such as methadone included in a thermoplastic elastomer matrix, for example, styrene-butadiene-styrene block copolymer matrix, styrene-block copolymer matrix isoprene-styrene, and the like, which may be present in a backing layer, and which were described above. In certain embodiments, a kit may include the topical methadone formulation and a macromolecular matrix such as a thermoplastic elastomer matrix and the like, for example, styrene-butadiene-styrene block copolymer matrix, styrene-isoprene-styrene block copolymer matrix , and the like, so that the matrix does not include any methadone (that is, the matrix can be a "blank methadone matrix").

The amount of the topical methadone formulation that is provided in one piece of equipment may be sufficient for a single application or for multiple applications. For example, where the formulation is present as a cream or the like, a suitable amount can be provided for multiple applications, for example, packed in a single container, for example, a single tube, bottle, flask, and the like, or one or packed individually in jars, tubes, and the like, separated. When the formulation is in the form of the drug transdermal delivery system with matrix / backing layer containing methadone, a plurality of transdermal drug delivery systems can be provided in a set with matrix / backing layer containing methadone, each packaged individually. In embodiments that have more than one transdermal delivery system of the matrix drug / backing layer containing methadone, a large number of transdermal delivery systems of the drug with matrix / backing layer containing methadone can be sealed together within a same packing. However, typically each transdermal delivery system of the matrix-containing drug / methadone-containing backup layer present in the equipment is sealed in a single package so that a transdermal drug delivery system with matrix / back-layer containing methadone can be removed from its packaging and used while the packaging of any other transdermal drug delivery system with matrix / backing layer containing methadone equipment remains intact or unopened. When a number of systems (or other form of topical methadone formulation) is provided, the dosage of methadone may vary, for example, for the application of a decreasing amount of methadone to a subject over time. Some or all of the components of the subject equipment can be packed in a suitable package to maintain sterility. In many modalities of the equipment of the subject, the components of the equipment are packaged in a container element of the equipment to make a single unit, easily manageable, where the container element of the equipment, for example, a box or analogous structure, may or may not be an airtight container, for example, to further preserve the sterility of some or all of the components of the equipment. The subject equipment may include instructions on how to use topical methadone formulations to deliver methadone to a subject to treat pain. The instructions can be recorded on a suitable medium or recording substrate. For example, instructions can be printed on a substrate, such as paper or plastic, etc. As such, the instructions can be present in the equipment as an insert in the package, in the container label of the equipment or in the components of the same (for example, associated with packaging or underpacking) etc. In other modalities, the instructions are present as a file of electronic storage data present in a suitable medium readable by computer, for example, CD-ROM, disk, etc. In other modalities, the actual instructions are not present in the equipment, but the means are provided to obtain the instructions from a remote source, for example, through the Internet. An example of this mode is a device that includes an electronic address in which instructions can be seen and / or from which instructions can be downloaded. As with the instructions, these means of obtaining instructions are recorded on a suitable substrate. The following examples are offered by way of illustration and not by way of limitation.

Experiments The following examples are set forth below to provide those of ordinary skill in the art with a complete discussion and description of how to make and use the present invention, and are not designed to limit competition from what the inventors consider their invention. Efforts have been made to ensure accuracy with respect to the numbers used (eg quantities, temperature, etc.), but some errors and experimental deviations must be considered. Unless stated otherwise, the parts are parts by weight, the molecular weight is the average molecular weight, the temperature is in degrees centigrade, and the pressure is equal to or close to atmospheric. 1. Solubility and stability of methadone in different solvents. In this experiment, the solubility of methadone in a number of different solvents was evaluated. The solvents evaluated were mineral oil, N-methyl-2-pyrrolidone, diisopropyl adipate, DEET, PEG, Di (propylene glycol), dehydrated alcohol and water. The solubility of the solutions was evaluated at 3 hours, 6 hours, 24 hours and 48 hours. The stability of the solutions was also evaluated.

Results Solubility Stability Tables 1A-1 E show the results of the stability of methadone in various solvents over a period of time, where Table 1A reports the results of time 0, Table 1B reports the results to one month, the table 1 C reports the results at two months, table 1 D reports the results at three months and table 1 E reports the results at six months. The samples were stored at 40 ° C / 75% RH. An HPLC test was performed.

TABLE 1A found concentration n average (mg / ml) is / ml) (mg / ml) (pttabilidad (mg ísu / pesu) N-methyl-2-pyrrolidone S1 1.0% 9.98 10.1 10.0 S1 1.0% 10.1 S2 1.0% 10.0 10.1 S2 1.0 % 9.99 Dissipate Adipate S1 1.0% 9.59 9.59 9.57 S1 1.0% 9.59 S2 1.0% 9.51 9.55 S2 1.0% 9.59 DEET (97%) S1 1.0% 8.84 8.84 8.84 S1 1.0% 8.84 S2 1.0% 8.91 8.85 S2 1.0% 8.79 Di ( propylene glycol) S1 1.0% 10.4 10.3 10.1 10.1 S1 1.0% 10.1 S2 1.0% 10.0 10.0 S2 1.0% 10.0 Dehydrated alcohol S1 1.0% 7.68 7.70 7.67 S1 1.0% 7.72 S2 1.0% 7.65 7.65 S2 1.0% 7.65 TABLE 1B One-month test of methadone / solvent samples for stability evaluation Solvent Sample Concentrate Concentration Concentration% initial No. average (mg / ml) found (mg / ml) (mg / ml) N-methyl- 2-pyrrolidone S1 10.0 5.88 5.87 58.7 S2 5.86 Adipate diisopropyl i S1 9.57 9.56 9.66 101 S2 9.76 DEET (97%) S1 8.84 8.92 9.04 102 S2 9.15 Di (propylene glycol) S1 10.1 9.57 9.60 95.0 S2 9.62 Dehydrated alcohol S1 7.67 7.84 7.78 101 S2 7.72 TABLE 1C Two-month test of methadone / solvent samples for stability evaluation I Solvent Sample Concentrate Concentration Ratio of initial ation found (mg / ml) (mg / ml) (mg / ml) Adipate diisopropyl S1 9.57 9.42 9.35 97.7 S2 9.28 DEET (97%) S1 8.84 8.42 8.45 95.6 S2 8.48 Di (propylene glycol) S1 10.1 9.63 9.79 96.9 S2 9.95 Dehydrated alcohol S1 7.67 7.47 7.54 98.2 S2 7.60 (: TABLE 1D Three-month test of methadone / solvent samples for stability evaluation Solvent Sample No. Concentrate Concentration Concentration% initial found average (mg / ml) (mg / ml) (mg / ml) Adipate S1 9.57 9.40 9.41 98.3 diisopropyl S2 9.41 S1 8.84 9.08 9.02 102 DEET (97%) S2 8.95 S1 10.1 9.65 9.60 95.0 Di (propylene glycol) S2 9.54 S1 7.67 7.53 7.52 98.0 Dehydrated 7.50 S2 alcohol TABLE 1E Six-month test of methadone / solvent samples for stability evaluation Solvent Sample No. Concentration Concentration Concentration% initial found average (mg / ml) (mg / ml) (mg / ml) Adipate S1 9.57 9.46 9.44 98.6 diisopropyl S2 9.42 S1 8.84 8.46 8.49 96.0 DEET (97%) S2 8.52 S1 10.1 9.68 9.66 95.6 Di (propylene glycol) S2 9.64 S1 7.67 7.46 7.59 97.7 Alcohol S2 7.52 dehydrated Conclusions The results above demonstrate the need for methadone to be in solution to pass through the skin. The solvent / carrier system used for this purpose must have the ability to solvate sufficient methadone for the desired effect, and at the same time provide a stable medium for the drug within the dosage form. Solubility data and stability data demonstrate the ability of certain solvents that can be used in the composition of a dosage form for methadone.

II. Concentrations of methadone in rat plasma - topical administration versus intravenous injection.

A. Study 1 i. Purpose The purpose of this study was to evaluate the pharmacokinetics of the methadone solution following intravenous and topical applications in a rat.

I. Experimental design Test Items: Test Item 1: Methadone from Teikoku Pharma USA, Inc. Test Item 2: Diisopropyl Methadone Adipate Solution (23.9%) from Teikoku Pharma USA, Inc. Test Item 3: Methadone-DEET Solution ( 10%) of Teikoku Pharma USA, Inc.

Sample preparation and dosing procedure: For Group A, a 0.5 mg / ml methadone solution was prepared, dissolving 1.3 mg of methadone powder in 2.6 ml of Sodium Chloride Injection (0.9%), USP. The pH of the solution was adjusted to 5 with 1 N HCl and 1 N NaOH to dissolve the methadone free base. The test article was administered intravenously (IV) through the tail vein to Group A animals. Injection was performed slowly. A gauze pad (1x1 cm) saturated with 0.2 ml of the appropriate test article was applied to the site attached to the back of the animals in Groups 2 and 3. The gauze pad was secured with occlusion tape. The animal was wrapped in gauze, which was secured in place with porous tape Zones. Blood collection: blood (0.5 ml) was collected in sodium heparin tubes at the appropriate points in time. The samples were centrifuged at approximately 2800 rpm at 2-8 degrees Celsius for approximately 15 minutes. The plasma was collected.

Results BQL = below the limit of quantification (1.00 ng / ml) Figure 1A provides a graphical representation of the results above. iv. Conclusions These data demonstrate that methadone is delivered through the skin of a rat in sufficient proportions to provide systemic levels of methadone that are known to cause analgesia, and at the same time this topical application was not irritating to the skin of the rat during the application time.

B. Study 2 i. Purpose The purpose of the study was to evaluate the pharmacokinetics of the methadone solution following intravenous and topical applications in a rat. ii. Experimental design Test articles: Test article 1: Methadone from Teikoku Pharma USA, Inc.

Test article 2: Diisopropyl methadone-adipate solution (23.9%) from Teikoku Pharma USA, Inc. Test item 3: Methadone-DEET solution (10%) from Teikoku Pharma USA, Inc.

Sample preparation and dosing procedure: For Group A, a 0.5 mg / ml methadone solution was prepared, dissolving 1.3 mg of methadone powder in 2.6 ml of Sodium Chloride Injection (0.9%), USP. The pH of the solution was adjusted to 5 with 1 N HCl and 1 N NaOH to dissolve the methadone free base. The test article was administered intravenously (IV) through the tail vein to Group A animals. Injection was performed slowly. A gauze pad (1x1 cm) saturated with 0.2 ml of the appropriate test article was applied to the site attached to the back of the animals in Groups 2 and 3. The gauze pad was secured with occlusion tape. The animal was wrapped in gauze, which was secured in place with porous tape Zones. Blood collection: blood (0.5 ml) was collected in sodium heparin tubes at the appropriate points in time. The samples were centrifuged at approximately 2800 rpm at 2-8 degrees Celsius for approximately 15 minutes. The plasma was collected. iii. Results These results are also provided in Figures 1 B and 1 C. iv. Conclusions The results above demonstrate the reproducibility of the data from the previous experiment (Study 1 above) and confirm the absence of irritation and the delivery of a sufficient amount of methadone to provide an analgesic response.

III. Pharmacokinetic study - Methadone formulation in human plasma Study A i. Purpose The purpose of this study was to evaluate the pharmacokinetics of the methadone solution after topical applications to a human. ii. Experimental design Test article: methadone-DEET solution (10.2%) Protocol: 50 mg of methadone free base was dissolved in 450 mg of DEET to produce the sample solution. Then a KIMWIPE (Kimberly-Clark) 7 cm x 7 cm in size with 500 mg of the test solution. Then the wet KIMWIPE with the test solution was applied on a human leg in the frontal area above the knee.

A sheet of aluminum was placed on the KIMWIPE. An adhesive was placed on the aluminum foil to hold the device in place on the leg of a 100 kg male human.

Plasma sample number Time point of blood collection H1 0 H2 4 hours H3 11 hours 50 minutes H4 22 hours 15 minutes iii. Results Concentrations of methadone in human plasma samples Sample (ng / mO Coagulation of the sample was not sufficiently prevented and H1 therefore no analysis was performed for the collection at 0 hours H2 Below the limit of quantification (1.00 ng / ml) H3 3.50 ng / ml H4 9.86 ng / ml iv. Conclusions The results of this experiment confirm that methadone it is substantially absorbed through the intact skin from a 10% solution in DEET. In addition, they demonstrate the absence of irritation for a human after a one-day application of topical methadone composition to the skin.

Study B Concentrations of methadone in human plasma samples Concentration information Sample time point (ng / ml) blood collection (hr) 1 5.36 12 2 4.95 18 3 2.24 139.5 Formulation used Content Weight% Styrene-isoprene-styrene copolymer 15 Hydrogen glycerol ester glycerol, KE311 10 Alicyclic saturated hydrocarbon resin, P100 30 Liquid paraffin 30 Methadone 10 DEET 5 Protocol 25 mg of methadone free base in patch of 5 x 5 cm. The application time was 12 hours. The patch was applied to a left human leg on the inside of the knee. The subject was a Malay man of 55 kg.

IV. Additional stability data.

A. Protocol.

Three samples of a topical patch of the methadone formulation F6 with a surface area of 2x2 cm were analyzed using the HPLC method. The analysis of each sample was repeated once to ensure accuracy.

Formulation F6 F6 Content Weight% SIS 20 KE311 25 P100 15 liquid paraffin 25 Methadone 10 DEET 5 'Total 100 HPLC conditions: Column: analytical Dionex Acclaim 120, C18, 3um Mobile phase: 40% acetonitrile, 60% potassium phosphate buffer with pH = 3.1, adjusted Flow ratio: 1 ml / min Column oven: 40 ° C Detector: 210 nm C. Results The stability of the patch formulation at 3 months at room temperature has an average recovery of 96.2%, assuming 100% recovery for the initial samples. The stability results of the formula at 6 months at room temperature show a value similar in recovery. It was found that the average recovery for the 6-month period was 96.4%.

Fórmí Recuperation Sample Condition #% 1 F6 # 1 / room temperature 3 months 94.3 1 repeat F6 # 1 / room temperature 3 months 93.7 2 F6 # 2 / room temperature 3 months 96.6 2 repeat F6 # 2 / room temperature 3 months 97.0 3 F6 # 3 / room temperature 3 months 97.5 3 repeat F6 # 3 / room temperature 3 months 98.0 4 F6 # 1 / room temperature 3 months 97.0 4 repeat F6 # 1 / room temperature 3 months 96.3 5 F6 # 2 / room temperature 3 months 95.2 5 repeat F6 # 2 / room temperature 3 months 95.6 6 F6 # 3 / room temperature 3 months 96.8 6 repeat F6 # 3 / room temperature 3 months 97.3 It is evident from the results and discussion above that the methods of the subject provide an improved method for treating pain, pain that can be treated through direct action on the μ-receptors at the pain site. The invention described above provides numerous advantages including ease of use and effective ways and efficient to deliver methadone topically to a subject to treat the subject for pain. The invention of the subject provides the rapid penetration of an effective amount of methadone through the surface of the skin, thereby providing rapid pain relief. The methods of the subject also provide a low-dose alternative for the systemic administration of methadone. In this way, the invention of the subject represents a significant contribution to the art. All publications and patents cited in this specification are incorporated herein by reference, as if each publication or individual patent was specifically and individually indicated to be incorporated as a reference. The mention of any publication is for discussion before the filing date and should not be considered as an admission that the present invention does not have the right to precede that publication by virtue of the prior invention. Although the foregoing invention has been described in some detail by way of illustration and example for the purpose of clarity of understanding, it is readily apparent to those of ordinary skill in the art, in light of the teachings of this invention, that certain changes and modifications thereto without departing from the spirit or competence of the appended claims.

Claims (23)

NOVELTY OF THE INVENTION CLAIMS

1. A method for administering a methadone agent to a subject, the method comprising: topically applying to a surface of the skin of the subject a formulation comprising a methadone agent as the only active agent present in the formulation for administering the methadone agent to the subject.

2. The method according to claim 1, further characterized in that the formulation comprises a matrix of thermoplastic elastomer.

3. The method according to claim 2, further characterized in that the matrix is a styrene-butadiene-styrene block copolymer matrix or a styrene-isoprene-styrene block copolymer matrix.

4. The method according to claim 2, further characterized in that the matrix is self-adhesive.

5. The method according to claim 2, further characterized in that the matrix is present on a backing layer.

6. - The method according to claim 5, further characterized in that the backing layer is substantially impermeable to the composite.

7. The method according to claim 1, further characterized in that the formulation comprises from about 0.1% to about 30.0% (weight / weight) of the methadone agent.

8. The method according to claim 1, further characterized in that the method is a method for treating the subject for pain.

9. The method according to claim 1, further characterized in that the topical formulation is a cream, gel, ointment or lotion.

10. A method for administering methadone to a subject, the method comprising: (a) contacting a surface of the subject's skin with a thermoplastic elastomeric matrix comprising the methadone agent; and (b) maintaining the matrix on that surface of the skin for a period of time sufficient for the methadone agent to be delivered to the subject.

11. The method according to claim 10, characterized in that the matrix is a styrene-butadiene-styrene block copolymer matrix or a styrene-isoprene-styrene block copolymer matrix.

12. - The method according to claim 10, further characterized in that the matrix is self-adhesive.

13. The method according to claim 12, further characterized in that the matrix is present on a backing layer.

14. The method according to claim 13, further characterized in that the backing layer is substantially impermeable to the pharmacological agent.

15. The method according to claim 10, further characterized in that the methadone agent is present in the matrix in an amount that is in a ratio of from about 0.1% to about 30.0% (w / w).

16. The method according to claim 10, further characterized in that this method is a method for treating the subject for pain.

17. A thermoplastic elastomer matrix comprising a methadone agent.

18. The matrix according to claim 17, further characterized in that the matrix is a styrene-butadiene-styrene block copolymer matrix or a styrene-isoprene-styrene block copolymer matrix.

19. The matrix according to claim 17, further characterized in that the matrix is self-adhesive.

20. - The matrix according to claim 17, further characterized in that the matrix is present on a backing layer.

21. The matrix according to claim 20, further characterized in that said backing layer is substantially impermeable to methadone.

22. The matrix according to claim 17, further characterized in that the methadone that is present in the matrix, it is in an amount within the ratio of from about 0.1% to about 30.0% (weight / weight).

23. A kit comprising: (a) a topical methadone formulation comprising a methadone agent, wherein said methadone is the only active agent present in that formulation; and (b) the instructions for practicing the method according to claim 1.